Transdermal delivery of drugs based on crystal size

ABSTRACT

A blend of at least two polymers in combination with a drug provides a pressure-sensitive adhesive composition for a transdermal drug delivery system in which the drug is delivered from the pressure-sensitive adhesive composition and through dermis when the pressure-sensitive adhesive composition is in contact with human skin. According to the invention, providing drug having differing crystal sizes as well as drug which is solublized in the pressure-sensitive adhesive composition controls the rate of drug delivery from the pressure-sensitive adhesive composition.

This application claims the benefit of provisional application60/617,561 filed Oct. 8, 2004, which is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

This invention relates generally to transdermal drug delivery systems,and more particularly to pharmaceutically acceptable adhesive matrixcompositions. The invention additionally relates to transdermal drugdelivery systems providing substantially zero order drug releaseprofiles for an extended period of time of up to seven days or longer.

BACKGROUND OF THE INVENTION

The use of transdermal drug delivery systems to topically administer anactive agent is well known. These systems incorporate the active agentinto a carrier composition, such as a polymeric and/orpressure-sensitive adhesive composition, from which the active agent isdelivered through the skin or mucosa of the user.

Active-ingredient-containing transdermal drug delivery systems(“patches”) are essentially divided into two major technical systems:reservoir systems and matrix systems. The present invention relates tomatrix systems where the active ingredient(s) are embedded in asemi-solid matrix made up of a single polymer or a blend of polymers.

Both types of devices employ a backing layer that forms the protectiveouter surface of the finished transdermal system and which is exposed tothe environment during use. A release liner or protective layer thatforms the inner surface covers the polymeric adhesive which is employedfor affixing the system to the skin or mucosa of a user. The releaseliner or protective layer is removed prior to application, exposing theadhesive, typically a pressure-sensitive adhesive.

In the “classic” reservoir-type device, the active agent is typicallydissolved or dispersed in a carrier to yield a non-finite carrier form,such as, for example, a fluid or gel. In the reservoir-type device, theactive agent is generally kept separate from the adhesive. The devicehas a pocket or “reservoir” which physically serves to hold the activeagent and carrier, and which is formed in or by a backing layer. Aperipheral adhesive layer is then used to affix the device to the user.

The reservoir-type devices have a number of disadvantages including anon-uniform drug release profile where a high dose of drug is initiallyreleased upon application to the user, often described as a “bursteffect.” This burst or high initial release of drug then drops off aftera period of time to a rate that necessary to achieve a therapeuticallyeffective amount. Drug delivery according to this profile is generallydescribed as first order release.

While classic reservoir-type devices are still in use today, the termreservoir is being used interchangeably herein with matrix-type deviceswhich still rely upon a separate adhesive means used to affix the deviceto the user.

In a matrix-type device, the active agent is dissolved or dispersed in acarrier that typically is in a finite carrier form. The carrier form canbe self-adhesive or non-adhesive. Non-adhesive matrix-type devices, thatis, those which still rely on a separate adhesive means to affix thedevice to the user, employ a drug permeable adhesive layer (oftenreferred to as an “in-line adhesive” since the drug must pass throughthis layer) applied over the drug matrix carrier layer. To bettercontrol the release rate of the drug, the non-adhesive matrix-typedevices often employ one or more additional drug permeable layers suchas, for example, rate controlling membranes. The non-adhesivematrix-type devices often contain excipients, such as drug deliveryenhancers, to help control the release rate. These devices are oftenreferred to as multilayer or multilaminate.

In a “monolithic” or “monolayer” matrix-type device, the active agent istypically solubilized or homogenously blended in an adhesive carriercomposition, typically a pressure-sensitive adhesive or bioadhesive,which functions as both the drug carrier and the means of affixing thesystem to the skin or mucosa. Such devices, commonly referred to asdrug-in-adhesive devices, are described, for example, in U.S. Pat. Nos.4,994,267; 5,446,070; 5,474,783 and 5,656,286, all of which are assignedto Noven Pharmaceuticals, Inc., Miami, Fla. and herein incorporated byreference.

While matrix-type devices, especially drug-in-adhesive devices, achievemore uniform and controlled drug deliver rates over longer periods oftime, most transdermal systems remain subject to a higher initial drugrelease than is required to achieve therapeutic efficacy. For many drugsand/or therapeutic situations, it would be advantageous to eliminate orsuppress this higher initial release and achieve a “steady state” (zeroorder) release profile which uniformly delivers a therapeuticallyeffective amount of drug over the extended duration of device's desireduse, preferably up to 7 days or more.

The high initial blood level concentration of certain drugs may causeadverse or undesired effects, or create toxicity concerns, therebylimiting the use of transdermal administration. In other instances, thehigher initial blood level concentration may reduce the amount of drugrequired for treatment to the point of risking under dosing, or thehigher initial blood level concentration may make it impractical toincrease the duration of the device's application while retainingtherapeutic effectiveness. Reducing the frequency of replacing thetransdermal drug delivery system would increase user compliance, reduceany lag or drop off in efficacious blood levels, and reduce the amountof drug required for treatment (also provided by reducing the higherinitial blood level associated with the higher release rate).

Drug concentration in transdermal delivery systems can vary widelydepending on the drug and polymers used. Low drug concentrations in theadhesive can result in difficulties in achieving an acceptable deliveryrate of the medicament, preferably one approximating zero orderkinetics. High drug concentrations, on the other hand, frequently affectthe adhesion properties of the adhesives, and tend to promote unwantedcrystallization and “burst effect” (i.e., rapid drug release).

Simple diffusion models for permeation of drugs through the skin suggestthat permeation rates are concentration dependent, that is, dependent onboth the amount and the degree of drug within the pressure-sensitiveadhesive composition. Some adhesives, such as, for example, polyacrylateadhesives have a high affinity for many drugs and thus tend tosolubilize higher concentrations of drug than do, for example, rubberadhesives. However, the use of polyacylates alone as the adhesive is notwithout its drawbacks as polyacrylate adhesives, for example, may tendto cause skin irritation, especially when the transdermal device is usedfor extended periods of time.

Various transdermal drug delivery systems have been described in theliterature. For example, U.S. Pat. No. 4,559,222 describes a multi-layernon-adhesive matrix-type device having a reservoir layer which comprisesmineral oil, colloidal silicon dioxide, a polyisobutylene adhesive and adrug, which may be clonidine, at a concentration greater thansaturation. The system includes a drug release rate controlling layerthrough which the drug may diffuse at a known rate, an adhesive layer,which may also contain a loading of drug, and a protective strippablecoating.

U.S. Pat. No. 5,762,952 describes a system comprising aself-crosslinking acrylate adhesive into which a drug, such asclonidine, is incorporated together with auxiliaries, such as solventsor absorption promoters, that are volatile at relatively hightemperatures. The patent discusses that the crosslinked acrylateadhesive is important to increase the consistency of the adhesivesubstance and to incorporate either a large amount of the active drug ora large amount of an inactive solubilizing agent into the adhesive.

Therefore, despite the existence of many different types of transdermaldelivery systems in the art, there remains a continuing need forimproving the release profile of drugs to achieve substantially zeroorder, as well as extending the duration of use of each individualtransdermal drug delivery system.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic representation of the effects on drug delivery,onset and profile of clonidine with different crystal sizes of the drugin pressure-sensitive adhesive compositions.

FIG. 2 is a graphic representation of the effects on drug delivery,onset and profile of frovatriptan with different crystal sizes of thedrug in pressure-sensitive adhesive compositions.

SUMMARY OF THE INVENTION

Based upon the foregoing, it is an object of the present invention toovercome the limitations of the prior transdermal systems, and toprovide a transdermal drug delivery system which allows modulation ofdrug permeation and delivery rates and profiles.

Another object is to provide a transdermal system, which is simple andinexpensive to manufacture. The present invention provides a transdermaldrug delivery system for the topical application of one or more'activeagents contained in one or more polymeric and/or adhesive carrier layerswhich is manufactured to optimize drug loading while providing desirableadhesion to skin or mucosa as well as providing modulation of the drugdelivery and profile.

The invention is also directed to compositions and methods ofcontrolling drug delivery rates, onset and profiles of at least oneactive agent in a transdermal delivery system by selectivelyincorporating in the transdermal drug delivery systems drugs in certaincrystallize size, alone or in combination with solubilized drug. Furthermanipulation of drug delivery, onset and profiles can be achieved byvarying the concentrations of the drug in the drug carrier.

Further embodiments of the invention include those described in thedetailed description.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The foregoing and other objects are achieved by this invention whichprovides a transdermal drug delivery system to provide an adhesivematrix composition which effectively delivers drugs to a user over anextended period of time.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains.

As used herein, the terms “blend” is used herein to mean that there isno, or substantially no, chemical reaction or crosslinking (other thansimple H-bonding) between the different polymers in the polymer matrix.However, crosslinking between a single polymer component is fullycontemplated to be within the scope of the present invention.

As used herein, the term “pressure-sensitive adhesive” refers to aviscoelastic material which adheres almost instantaneously to mostsubstrates with the application of very slight pressure and remainspermanently tacky. A polymer is a pressure-sensitive adhesive within themeaning of the term as used herein if it has the properties of apressure-sensitive adhesive per se or functions as a pressure-sensitiveadhesive by admixture with tackifiers, plasticizers or other additives.The term pressure-sensitive adhesive also includes mixtures of differentpolymers and mixtures of polymers, such as polyisobutylenes (PIB) ofdifferent molecular weights, the resultant mixtures being apressure-sensitive adhesive. In the last case, the polymers of lowermolecular weight in the mixture are not considered to be “tackifiers,”the term “tackifier” being reserved for additives which differ otherthan in molecular weight from the polymers to which they are added.

The term “topical” or “topically” is used herein in its conventionalmeaning as referring to direct contact with an anatomical site orsurface area on a mammal including skin, teeth, nails and mucosa.

The term “mucosa” as used herein means any moist anatomical membrane orsurface on a mammal such as oral, buccal, vaginal, rectal, nasal orophthalmic surfaces.

The term “transdermal” as used herein means passage into and/or throughskin or mucosa for localized or systemic delivery of an active agent.

The term “solubilized” is intended to mean that in the carriercomposition there is an intimate dispersion or dissolution of the activeagent at the crystalline, molecular or ionic level. As such, thesolublized active agent is considered herein to be in “non-crystallized”form when in the compositions of the present invention.

As used herein “flux” is defined as the percutaneous absorption of drugsthrough the skirt, and is described by Fick's first law of diffusion:J=D(dC _(m) /dx),

where J is the flux in g/cm²/sec, D is the diffusion coefficient of thedrug through the skin in cm²/sec and dC_(m)/dx is the concentrationgradient of the active agent across the skin or mucosa.

The phrase “pharmaceutically acceptable flexible, finite” is intended tomean a solid form capable of conforming to a surface to which it isapplied, and which is capable of maintaining the contact in such solidform so as to facilitate topical application without adversephysiological response, and without being appreciably decomposed byaqueous contact during use by a subject.

The term “user” or “subject” is intended to include all warm-bloodedmammals, preferably humans.

The phrase “substantially zero-order” as used herein means transdermaldelivery of an active agent at a release rate which is approximatelyconstant once steady state is attained, typically within 12 to 24 hoursafter topical application. While variability in blood levels of activeagent are contemplated within the scope of this meaning once steadystate release is attained, the depletion rate of active agent over theduration of use should typically not exceed about 20% to about 25%.

The term “active agent” (and its equivalents “agent,” “drug,”“medicament” and “pharmaceutical”) is intended to have the broadestmeaning and includes at least one of any therapeutic, prophylactic,pharmacological or physiological active substance, cosmetic and personalcare preparations, and mixtures thereof, which is delivered to a mammalto produce a desired, usually beneficial, effect. More specifically, anyactive agent that is capable of producing a pharmacological response,localized or systemic, irrespective of whether therapeutic, diagnostic,cosmetic or prophylactic in nature, is within the contemplation of theinvention. Also within the invention are such bioactive agents aspesticides, insect repellents, sun screens, cosmetic agents, etc. Itshould be noted that the drugs and/or bioactive agents may be usedsingularly or as a mixture of two or more such agents, and in amountssufficient to prevent, cure, diagnose or treat a disease or othercondition, as the case may be. In the case of drugs, the drug can be inits free base or acid form, or in the form of salts, esters, amides,prodrugs, enantiomers or mixtures thereof, or any otherpharmacologically acceptable derivatives, or as components of molecularcomplexes

The drug is used in a “pharmacologically effective amount.” This termmeans that the concentration of the drug is such that in the compositionit results in a therapeutic level of drug delivered over the term thatthe transdermal dosage form is to be used, preferably with zero orderkinetics. Such delivery is dependent on a great number of variablesincluding the drug, the time period for which the individual dosage unitis to be used, the flux rate of the drug from the system and a number ofother variables. The amount of drug needed can be experimentallydetermined based on the flux rate of the drug through the system andthrough the skin when used with and without enhancers. Having determinedthe flux rate needed, the transdermal delivery system is designed sothat the release rate over the period of time of therapeutic use will beat least equal to the flux rate. Of course, the surface area of thetransdermal delivery system also affects the delivery of the drug fromthe system.

Drugs in general can be used in this invention. These drugs includethose categories and species of drugs set forth on page ther-5 tother-29 of the Merck Index, 11th Edition Merck & Co. Rahway, N.J.(1989). Preferred drugs and pro-drugs are those that have somesolubility in water and oil according to their octanol-water partitioncoefficient, a physical property used extensively to describe acompound's lipophilic or hydrophobic properties. The logarithm log P iscommonly used to characterize its value. Such preferred drugs orprodrugs have log P values from about 0 to about 4, more preferably fromabout 0 to about 3, and most preferably from about 0 to about 2.5, ascalculated using EPA Software KOWWIN version 1.67.

Particularly preferred drugs include oxymorphone, caffeine, zidovudine,pilocarpine, ranitidine, lazabemide, thiopental, scopolamine,butabarbital, digoxin, tiapride, pemoline, diclofenac, antipyrine,albuterol, oxycodone, terbutaline, ephedrine, pseudoephedrine, morphine,captopril, mescaline, naloxone, phenelzine, secobarbital, flumazenil,fluvastatin; sumatriptan, oxcarbazepine, modafinil, moclobemide,nadolol, aldosterone, pentaerythritol, prazosin, ramipril, guanfacine,physostigmine, phenobarbital, minoxidil, aprobarbital, naltrexone,leflunomide, terazosin, pindolol, fludrocortisone, mephobarbital,profentofylline, methysergide, transylcypromine, prednisone,hydromorphone, dantrolene, hydrocortisone, talipexole, lidocaine,metoprolol, betamethasone, timolol, lesopitron, benzocaine, clobazam,colchicine, butalbital, prilocalne, atropine, mepivacaine, procaine,pentobarbital, amobarbital, clorazepate, yohimbine, temazepam,hydrocodone, phenyloin, trimethobenzamide, warfarin, carbamazepam,nedociomil, buspirone, ketorolac, oxazepam, piribedil, pramipexole,secobarbital, hydrocortisone, lorazepam, chlordiazepoxide, quetiapine,enalapril, betamethasone acetate, tamsulosin, nifedipine, ergotamine,clonazepam, atorvastatin, tolmetin, bumetanide, piroxicam, perindopril,propranolol, mexiletene, chlorzoxazone, indapamide, diazepam,ciciopirox, ramipril, amphetamine, benztropine, methylphenidate,apomorphine, diltiazem, alprenolol, clozapine, ropivacaine, valproicacid, norethindrone, ketoprofen, tramadol, tetracaine, etorphine,flurazepam, meperidine, ropinirole, carvedilol, bupranolol, pravastatin,naproxen, diphenhydramine, ketamine, albendazole, idebenone, tacrine,finasteride, nabumetone, gestodene, testosterone, venlafaxine,estazolam, rimantadine, phentolamine, propafenone, levorphanol,bupivicaine, perindopril, droperidol, celecoxib, norgestrel, isradipine,risperidone, benazepril, loratidine, betamethasone, progesterone,butorphanol, papaverine, quinapril, alprostadil, prostaglandin,citalopram, ibuprofen, flurbiprofen, chlorpheniramine, zolpidem,alprazolam, fentanyl, nisoldipine, benztropine, betamethasone, etodolac,tibolone, estradiol, adamantane, chlormadinine, oxybutynin, triazolam,doxepin, prazepam, capsaicin, granisetron, frovatriptan andnorethindrone acetate.

The drugs and mixtures thereof can be present in the composition indifferent forms, depending on which form yields the optimum deliverycharacteristics. Thus, in the case of drugs, the drug can be in its freebase or acid form, or in the form of salts, esters, or any otherpharmacologically acceptable derivatives, or as components of molecularcomplexes.

The amount of drug to be incorporated in the composition variesdepending on the particular drug, the desired therapeutic effect, andthe time span for which the device is to provide therapy. For mostdrugs, the passage of the drugs through the skin will be therate-limiting step in delivery. Thus, the amount of drug and the rate ofrelease is typically selected so as to provide transdermal deliverycharacterized by a zero order time dependency for a prolonged period oftime. The minimum amount of drug in the system is selected based on theamount of drug which passes through the skin in the time span for whichthe device is to provide therapy. Normally, the amount of drug in thesystem can vary from about 0.01% to about 50%. However, the compositionof this invention is particularly useful for drugs which are used inrelatively low concentrations, especially 0.1% to 30% of the totalcomposition, more preferably from about 0.5% to about 15% of the totalcomposition, most preferably from about 1% to about 10% of the totalcomposition. For certain drugs, like frovatriptan, the preferredconcentration is in the range of about 15% to about 20% by weight of thetotal composition.

Particularly preferred drugs include scopolamine, estradiol,granisetron, frovatriptan and clonidine. Clonidine is ananti-sympathicotonic agent having an imidazoline structure. It hasaffinity for α₁-adrenoceptors and—more strongly—for pre- andpost-synaptic α₂-adrenoceptors and lowers peripheral sympathetic tone.It is believed that clonidine lowers blood pressure by decreasingcardiac output and—in the case of prolonged medication—by reducingperipheral vascular resistance. At the same time, it is believed thatclonidine reduces the release of renin with a decrease in angiotensin IIin the blood plasma, with aldosterone being released from the adrenalcortex.

Clonidine may be used, for example, in treating the followingindications: hypertension, migraine, anxiety states, hyperkineticbehavioural disorders, withdrawal symptoms in alcohol or drugwithdrawal, and menopausal symptoms.

Clonidine hydrochloride exists in the form of a mesomeric component. Thechemical name is 2-(2,6-dichlorophenylamino)-2-imidazolinehydrochloride. Clonidine has the following molecular formula:C₉H₉Cl₂N₃HCl, and a molecular weight of 266.56.

In transdermal drug delivery systems, the presence of crystals (drugs orother additives or both) is generally undesirable. Typically, if thedrug is present in crystalline form, it is not available for releasefrom the system, and therefore not available for delivery. Moreover,although drug crystals can first dissolve and then release from thesystem, such a process is usually rate limiting and tends to reducetransdermal permeation rates or provide non-controlled delivery rates orprofiles.

In the present invention, the drug is incorporated or dispersed incrystalline form in the transdermal system carrier composition. Thecrystalline form used comprises two sizes—small and larger crystals—andmay be present singularly or in combination depending on the desiredflux and delivery rates and profiles. Optionally, an amount of the drugcan also be present in non-crystalline or solubilized form where shortand/or quick drug onset is also desired. Accordingly, the drug may bewholly insoluble in the carrier or adhesive composition, or partiallysoluble.

As used herein, the term “small crystal size” is intended to refer to adrug which is present in the transdermal drug delivery system in aparticle size of from about 1 μm to about 200 μm and more preferablyfrom about 10 μm to about 200 μm.

The term “larger crystal size” is intended to refer to a drug which ispresent in the transdermal drug delivery system in a particle size whichis greater than the small crystal size. In other words, for example,where a first crystal size of 75 μm is used, the larger crystal size maybe 100 μm. When used in conjunction with solubilized drug or alone,particularly to achieve prolonged or extended delivery, examples oflarger crystal size are from about 100 μm to about 2000 μm, and morepreferably from about 100 μm to about 1000 μm.

In general, therapeutic amounts of drug can be delivered from thetransdermal drug delivery system containing about 0.1% to about 50% byweight of drug. However, the transdermal drug delivery system of thisinvention is particularly useful for drugs which are used in relativelylow concentrations, especially from about 0.3% to about 30% of the totaltransdermal drug delivery system, more preferably from about 0.5% toabout 20% of the total transdermal drug delivery system, most preferablyfrom about 1% to about 15% of the total transdermal drug deliverysystem.

As set forth above, the drug may be present in the same transdermal drugdelivery system in three different forms—solubilized in the transdermaldrug delivery system, in small crystal size and in larger crystal size.The solubilized drug is present in the transdermal drug delivery systemin an amount of from about 0.1% to about 50% by weight of the total drugamount, the small crystal size drug is present in an amount of fromabout 1% to about 60% by weight of the total drug amount, and the largercrystal size drug is present in an amount of from about 2% to about 70%by weight of the total drug amount.

The desired ratio of small crystal size drug to larger crystal size drugis generally from about 2:1.

The invention resulted from the discovery that the transdermalpermeation rate of a drug from a carrier composition can be selectivelymodulated by adjusting the drug crystal size and distribution ratherthan exclusively the solubility of the drug in the system, in order toachieve maximum delivery of drug. As used herein, the term “transdermalpermeation rate” means the rate of passage of the drug through the skin;which, as known in the art, may or may not be affected by the rate ofrelease of the drug from the carrier.

In addition to selecting the crystal size of the drug where the presenceof solubilized drug is also desired, the selection of the polymeric oradhesive carrier is equally important in order to advantageously providea selectable modulation of the delivery rate of the drug and requiringadjusting the net solubility of the drug in the carrier composition.

Solubility parameter, also referred to herein as “SP,” has been definedas the sum of all the intermolecular attractive forces, which areempirically related to the extent of mutual solubility of many chemicalspecies. A general discussion of solubility parameters is found in anarticle by Vaughan, “Using Solubility Parameters in CosmeticsFormulation,” J. Soc. Cosmet. Chem., Vol. 36, pages 319-333 (1985).

The active agent in crystalline form or both crystalline and dissolvedform is dispersed or dispersed and solubilized in a carrier. The term“carrier” as used herein refers to any non-aqueous material known in theart as suitable for transdermal drug delivery administration, andincludes any material into which an active agent may be dispersed and/orsolubilized in combination or admixture with the other ingredients ofthe composition.

The polymeric materials preferably comprise adhesives and, inparticular, pressure-sensitive adhesives. An “adhesive” as used hereinmeans any natural or synthetic material that is capable of sticking tothe site of topical application. The term “pressure-sensitive adhesive”as used herein refers to an adhesive which adheres instantaneously tomost surfaces with the application of very slight pressure and remainspermanently tacky. An adhesive is a pressure-sensitive adhesive withinthe meaning of that term as used herein if it has the properties of anadhesive pressure-sensitive adhesive per se or functions as the same byadmixture with tackifiers, plasticizers, cross-linking agents or otheradditives.

The carrier material is typically used in an amount of about 20% toabout 98%, and preferably from about 30% to about 95%, and mostpreferably about 40% to about 95% by weight based on the dry weight ofthe total carrier composition. The term “carrier composition” may alsorefer to enhancers, solvents, co-solvents and other types of addictivesuseful for facilitating transdermal drug delivery.

Suitable carrier materials include all of the non-toxic natural andsynthetic polymers known for or suitable for use in transdermal systems,such as solvent-based, hot melt and grafted adhesives, and may be usedalone or in combinations, mixtures or blends. Examples include acrylicpolymers, gums, silicone-based polymers (broadly referred to as“polysiloxanes” and including silicone fluids) and rubber-based polymersthat include hydrocarbon polymers such as natural and syntheticpolyisoprene; polybutylene; polyisobutylene; styrene based polymers;styrene block copolymers; butadiene based polymers; styrene/butadienepolymers; styrene-isoprene-styrene block copolymers; hydrocarbonpolymers such as, for example, butyl rubber; halogen-containing polymerssuch as, for example, polyacrylonitrile, polytetrafluoroethylene,polyvinylchloride, polyvinylidene chloride, and polychlorodieneaspolyisobutylenes, polybutylenes, ethylene/vinyl acetate and vinylacetate based adhesives, styrene/butadiene adhesives, polyisoprenes,styrenes and styrene block copolymers and block amide copolymers, andbioadhesives set forth in U.S. Pat. No. 6,562,363 which is expresslyincorporated by reference in its entirety.

Suitable polysiloxanes include silicone pressure-sensitive adhesiveswhich are based on two major components: a polymer, or gum, and atackifying resin. The polysiloxane adhesive is usually prepared bycross-linking the gum, typically a high molecular weightpolydiorganosiloxane, with the resin, to produce a three-dimensionalsilicate structure, via a condensation reaction in an appropriateorganic solvent. The ratio of resin to polymer is the most importantfactor which can be adjusted in order to modify the physical propertiesof polysiloxane adhesives. Sobieski, et al., “Silicone PressureSensitive Adhesives,” Handbook of Pressure-Sensitive AdhesiveTechnology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold,N.Y. (1989). Use of capped (or amine-compatible) polysiloxanes are oftenpreferred to increase drug stability and reduce degradation.

Further details and examples of silicone pressure-sensitive adhesiveswhich are useful in the practice of this invention are described in thefollowing U.S. Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767.Suitable silicone pressure-sensitive adhesives are commerciallyavailable and include the silicone adhesives sold under the trademarksBIO-PSA® by Dow Corning Corporation, Medical Products, Midland, Mich.

In particularly preferred embodiments of the invention, the carriermatrix composition comprises a pressure-sensitive adhesive, and morepreferably a blend of one or more acrylic, polysiloxane and/orrubber-based polymers, particularly polyisobutylene.

The term “acrylic polymer” is intended to be used interchangeably withthe terms acrylate polymer, polyacrylate and polyacrylic adhesivepolymers as used herein and as known in the art.

The acrylic polymers useful in practicing the invention are polymers ofone or more monomers of acrylic acids and other copolymerizablemonomers. The acrylic polymers also include copolymers of alkylacrylates and/or methacrylates and/or copolymerizable secondary monomersor monomers with functional groups, thus providing eithernon-functional/reactive or functional/reactive acrylic-based polymers.By varying the amount of each type of monomer added, the cohesiveproperties of the resulting acrylic polymer and/or the resulting acrylicpolymer's effect on drug stability can be changed as is known in theart. In general, the acrylic polymer is composed of at least 50% byweight of an acrylate or alkyl acrylate monomer, from 0 to 20% of afunctional monomer copolymerizable with the acrylate, and from 0 to 40%of other monomers.

Acrylate monomers which can be used include acrylic acid, methacrylicacid, butyl acrylate, methacrylate, methyl methacrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate,2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate,isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate,decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecylmethacrylate, tridecyl acrylate, and tridecyl methacrylate.

Functional monomers, copolymerizable with the above alkyl acrylates ormethacrylates, which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate and other monomershaving at least one unsaturated double bond which participates incopolymerization reaction in one molecule and a functional group on itsside chain such as a carboxyl group, a hydroxyl group, a sulfoxyl group,an amino group, an amino group and an alkoxyl, as well as a variety ofother monmeric units including alkylene, hydroxy-substituted alkylene,carboxylic acid-substituted alkylene, vynylalkanoate, vinylpyrrolidone,vinylpyridine, vinylpirazine, vinylpyrrole, vinylimidazole,vinylcaprolactam, vinyloxazole, vyinlacate, vinylpropionate andvinylmorpholine.

Further details and examples of acrylic adhesives which are suitable inthe practice of the invention are described in Satas, “AcrylicAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2.sup.nded., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y. (1989).

Suitable acrylic adhesives are commercially available and include thepolyacrylate adhesives sold under the trademarks DURO-TAK.® by NationalStarch Company, Bridgewater, N.J.; GELVA® by Cytec Surface Specialties,St. Louis, Mo.; and EUDRAGIT® by Roehm Pharma GmbH, Darmstadt, FederalRepublic of Germany.

In the practice of preferred embodiments of the invention, the rubberbased polymer, acrylic based polymer or polysiloxane polymer, ormixtures thereof constitutes from about 5% to about 97% of the totalweight of the composition, preferably about 12% to about 97%, and morepreferably from about 14% to about 94%, and most preferably from about18 to 90% of the total weight of the carrier material. The choice of thespecific polymers for the pressure sensitive adhesive composition isdependent on the type of drug used in the transdermal drug deliverysystem.

The rubber-based pressure sensitive adhesive can be blended with apolydiorganosiloxane polymer. By “polydiorganosiloxane polymer” is meanta silicone fluid polymer having repeat units of the formula R₂SiO_(2/2)siloxy units where R is a hydrocarbon or substituted hydrocarbon havingfrom about 1 to 20 carbons atoms and is represented by the formula:(R)₃Si—O—[(R)₂Si—O—]_(n)Si(R)₃

where R can be a hydrocarbon or substituted hydrocarbon of 1 to about 20carbon atoms and can be selected from the group consisting of alkyl,aryl, cycloalkyl and the like which may be substituted to containhalogen, amino, hydroxy, ether or other similar functionalities. Theinteger “n” is sufficient to cause the silicone fluid to have aviscosity of between about 20 and 25,000 centistokes. Preferably theviscosity will be between about 20 and 12,500 centistokes. The term“polydiorganosiloxane polymer” and silicone fluid polymer are usedinterchangeably herein.

With reference to the above formula, preferably R is methyl and thediorganopolysiloxane is a dimethylpolysiloxane polymer generically knownas dimethicone. Therefore the terms “polydimethylsiloxane” and“dimethicone” are used interchangeably and refer to the preferreddiorganopolysiloxane polymer.

Polydiorganosiloxane polymer fluids may be generally classified asunmodified silicones, linear and cyclic volatile silicones, alkyl/alkoxymodified silicones, phenyl modified silicones, aminofunctionalizedsilicones, polyglucoside silicones and polyether functionalizedsilicones.

Exemplary of unmodified silicone fluid polymers suitable for use in thepresent invention are Dimethicone and Dimethiconol available as SP 96®(20, 50-1000), Visasil® (5M-100M) and SF18(350) from Costec Inc.(Palatine, Ill.), Dow Corning® 200 and 225 fluids from Dow CorningCorporation (Midland, Mich.), DM 100-1000, AK 5-1MM, X-345 and F-1006from Wacker Silicones Corporation (Adrian, Mich.) and Sentry DimethiconeNF from Whitco Corporation (Greenwich, Conn.).

Representative examples of linear and cyclic volatile silicones suitablefor use in the present invention are Cyclomethicone (>4) available as SF1173, SF 1202 and SF 1204 from Costec Inc., Dow Corning® 244, 145, 344and 345 fluids from Dow Corning Corporation and CM 040 from WackerSilicone Corporation; Dimethicone SF96® (5) from Costec Inc. andWacker-Besil DM 1 plus from Wacker Silicones Corporation; andHexamethyldisiloxane available as Wacker-Besil DM 0.65 from WackerSilicones Corporation.

Examples of alkyl/alkoxy modified silicones suitable for use in thepresent invention include lauryl dimethicone available as Dow Corning®Q2-5200 from Dow Corning Corp, LDM 3107VP from Wacker Silicones Corp.;Cetyl dimethicone available as Dow Corning® 2502 from Dow Corning Corp.and DMC 3071 from Wacker Silicones Corp.; Stearyl dimethicone availableas SF1632 from Costec, Inc., Dow Corning® 2504 from Dow Corning Corp.,and E32 from Wacker Silicones Corporation.

Illustrative of phenyl modified silicones suitable for use in thepresent invention are Phenyltrimeticone which as available as SF 1550from Costec Inc., Dow Corning® 556 fluid from Dow Corning Corporationand PDM 20, 100, 1000 from Wacker Silicones Corporation.

Amino-functionalized silicones suitable for use in the present inventioninclude, for example, Amodimethicone available as SM2658 from Costec,Inc., Dow Corning® 929 and 939 from Dow Corning Corp. and L650, 652 andADM 6057E from Wacker Silicones Corporation;Trimethylsilylamodimethicone available as SF1708-D1, SM2101 andSM2115-D2 from Costec, Inc. Dow Corning® Q2-7224 and Q2-8220 from DowCorning Corp. and L653, 655, 656 and ADM 3047E from Wacker SiliconesCorporation.

Examples of the class of silicone polyglucosides suitable for use in thepresent invention is Octyl Dimethicone Ethoxy Glucoside (SPG 128) fromWacker Silicones Corporation.

Examples of polyether functionalized silicones suitable for use in thepresent invention include Dimethicone Copolyol available as SF 1188 fromCostec, Inc. Dow Corning® 2501, 3225C, Q2-5324 and Q2-5434 from DownCorning Corp. and DMC 6032 and Cetyl Dimethicone Copolyol available asCMC 3071 from Wacker Silicones Corporation.

The above are representative and it should be understood that anypolydiorganosiloxane polymer fluid functional for use in adjusting theadhesive properties of a pressure-sensitive adhesive may be utilized.

The amount of silicone fluid polymer in the pressure-sensitive adhesivemay vary over a wide range as long as it effectively regulates orcontrols the degree of tackiness such that the adhesive retains thetransdermal device on the skin of a subject for the desired period oftime and yet allows for the efficient removal of the device with no orminimal skin irritation or damage. Preferred amounts of silicone fluidpolymer are from about 0.5 to about 25% of the total weight of thepressure sensitive adhesive composition, preferably from about 2 toabout 10% of the total weight of the pressure sensitive adhesivecomposition, more preferably from about 5 to about 8.5% of the totalweight of the pressure sensitive adhesive composition, and mostpreferably about 6.5% of the total weight of the pressure sensitiveadhesive composition.

The weight per unit area of the dried contact adhesive layer (matrix) isusually in the range of from about 1 mg/cm² to about 20 mg/cm², and morepreferably in the range of from about 2.5 mg/cm² to about 15 mg/cm². Thedelivery rate is in the range of from about 0.01 mg to about 100 mg ofactive agent per day, and more preferably in the range of from about 0.1mg to about 50 mg per day. Generally, the amount of drug is thatsufficient to deliver a therapeutically effective amount of the activeagent at a substantially zero-order kinetic rate of delivery for anextended period of time of at least three days and up to seven days orlonger.

While not wishing to be bound by theory, it is believed that afterapplication of the transdermal drug delivery device to the skin ormucosa of the user, any drug present in solubilized form in the carrieris transdermally delivered, typically at first order kinetics, fasterthan the small crystal size drug which is subsequently solublized in andfrom the moisture of the user's skin or mucosa to next deliver a secondamount of drug transdermally across the skin or mucosa of the user.Finally, the larger crystal size drug in the carrier is transdermallydelivered across the skin or mucosa of the user providing extended orprolonged therapy. As an example, for a seven day transdermal deliverydevice, the drug is delivered as set forth below:

Drug Form Type Drug Delivery Time (Hours) Solubilized Drug 0-40 SmallCrystal Drug 6-85 Larger Crystal Drug 65-168

As is understood by the person having ordinary skill in this art, bytailoring the type of drug, the makeup of the carrier composition, thecrystalline size(s) of the drug, the amount of drug, the ratio of thesmall and larger crystal drug size, and the amount of solubilized drugin the carrier composition and, optionally, even encapsulating the drugcrystals, the transdermal drug delivery device can be tailored todeliver drug to a user over a prolonged period of topicaladministration, i.e., up to 7 days or longer.

Those skilled in the art can readily determine the rate of delivery ofdrugs from the carrier composition in order to select suitablecombination(s) of polymers and drug for a particular application.Various techniques can be used to determine the rate of delivery of thedrug from the carrier. Illustratively, the rate of delivery can bedetermined by measuring the transfer of drug from one chamber to anotherthrough cadaver skin over time, and calculating, from the obtained data,the drug delivery or flux rate.

Of course, the carrier composition of the transdermal drug deliverysystem can also contain agents known to accelerate the delivery of thedrug through the skin. These agents have been referred to as skinpenetration enhancers, accelerants, adjuvants, and sorption promoters,and are collectively referred to herein as “enhancers.” This class ofagents includes those with diverse mechanisms of action including thosewhich have the function of improving the solubility and diffusibility ofthe drug within the multiple polymer and those which improvepercutaneous absorption, for example, by changing the ability of thestratum corneum to retain moisture, softening the skin, improving theskin's permeability, acting as penetration assistants or hair-follicleopeners or changing the state of the skin including the boundary layer.Some of these agents have more than one mechanism of action, but inessence they serve to enhance the delivery of the drug. An enhancer maybe included in a drug delivery system up then the enhancer is preferablypresent in an amount of about 1% to about 10% by weight. Some examplesof enhancers are polyhydric alcohols such as dipropylene glycol,propylene glycol, and polyethylene glycol which enhance drug solubility;oils such as olive oil, squalene, and lanolin; polyethylene glycolethers and fatty ethers such as cetyl ether and oleyl ether; fatty acidesters such as isopropyl myristate which enhance drug diffusibility;fatty acid alcohols such as oleyl alcohol; urea and urea derivativessuch as allantoin which affect the ability of keratin to retainmoisture; polar solvents such as dimethyldecylphosphoxide,methyloctylsulfoxide, dimethyllaurylamide, dodecylpyrrolidone,isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide,and dimethylformamide which affect keratin permeability; salicylic acidwhich softens the keratin; amino acids which are penetration assistants;benzyl nicotinate which is a hair follicle opener; and higher molecularweight aliphatic surf actants such as lauryl sulfate salts which changethe surface state of the skin and drugs administered. Other agentsinclude oleic and linoleic acids, ascorbic acid, panthenol, butylatedhydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate,propyl oleate, isopropyl palmitate, oleamide, polyoxyethylene (4) laurylether, polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleylether sold under the trademarks Brij 30, 93 and 97 by ICI Americas,Inc., and polysorbate 20 sold under the trademark Tween 20 by IdAmericas, Inc.

In certain embodiments of the invention a plasticizer or tackifyingagent is incorporated into the formulation to improve the adhesivecharacteristics of the pressure-sensitive adhesive composition. Atackifying agent is particularly useful in those embodiments in whichthe drug does not plasticize the polymer. Suitable tackifying agents arethose known in the art including: (1) aliphatic hydrocarbons; (2) mixedaliphatic and aromatic hydrocarbons; (3) aromatic hydrocarbons; (4)substituted aromatic hydrocarbons; (5) hydrogenated esters; (6)polyterpenes; and (7) hydrogenated wood resins or rosins. The tackifyingagent employed is preferably compatible with the blend of polymers. Inpreferred embodiments, the tackifying agent is silicone fluid (e.g., 360Medical Fluid, available from Dow Corning Corporation, Midland, Mich.)or mineral oil. Silicone fluid is useful for blends comprisingpolysiloxane as a major component. In other embodiments, where asynthetic rubber, for example, is a major component, mineral oil is apreferred tackifying agent. Acrylics can be tackified with oleates,oleic acid, oleyl alcohol and other fatty acid-derived agents.

For drug molecules which are not readily soluble in the carrier polymersystem, a co-solvent for the drug and polymer can be added. Co-solvents,such as lecithin, retinol derivatives, tocopherol, dipropylene glycol,triacetin, propylene glycol, saturated and unsaturated fatty acids,mineral oil, silicone fluid, alcohols, butyl benzyl phthalate, and thelike are useful in the practice of the instant invention depending onthe net solubility of the drug in the carrier composition.

The compositions of this invention may further be provided with variousthickeners, fillers and other additives known for use with transdermaldrug delivery systems.

In a device aspect of the invention, the pressure-sensitive adhesivecomposition can be used as an adhesive portion of any transdermal drugdelivery system (e.g., a reservoir device) or it can comprise anadhesive monolithic. Of course, the principles of the invention wouldstill apply to embodiments where the transdermal drug deliverycomposition is not a pressure-sensitive adhesive and comprises a drugreservoir.

A device, or individual dosage unit, of the present invention can beproduced in any manner known to those of skill in the art. After thedermal composition is formed, it may be brought into contact with anocclusive backing layer in any manner known to those of skill in theart. Such techniques include calendar coating, hot melt coating,solution coating, etc. Of course, occlusive backing materials are wellknown in the art and can comprise plastic films of polyethylene, vinylacetate resins, polyester, polypropylene, BAREX®, ethylene/vinyl acetatecopolymers, polyvinyl chloride, polyurethane, and the like, metal foils,non-woven fabric, cloth, coextrusions or laminations of the above andcommercially available laminates. The occlusive backing materialgenerally has a thickness in the range of 2 to 1000 micrometers and thedermal composition is generally disposed on backing material in athickness ranging from about 12 to 250 micrometers thick.

Suitable release liners are also well known in the art and include thecommercially available products of Release International designatedBio-Release® liner and Syl-off® 7610 liner. For preferred embodiments inwhich a polysiloxane is part of the multiple polymer adhesive system,the release liner must be compatible with the silicone adhesive. Anexample of a suitable commercially available liner is 3M's 1022 ScotchPak®.

In a method aspect of the invention, a plurality of polymers are blended(but not chemically reacted or cross-linked) to result in apressure-sensitive adhesive composition which controls delivery of anincorporated drug through the skin or mucosa. The term “blending,” ofcourse, incorporates choosing the appropriate polymeric components, andthe proportions thereof, to achieve the desired effect.

Drug is blended with the pressure sensitive adhesives to solubilize thedrug into the pressure sensitive adhesive composition. Crystallized drugis then added to the composition. Customary substances such as fillers,skin-protective substances, tackifiers or the like may be added ifdesired, but it is not essential. The mixture is then blended togetherto form a flexible, finite composition. The system is freed of solventin a dryer located downstream. After leaving the dryer, the then dry andself-adhesive active ingredient/adhesive matrix is laminated with afurther layer, which may be e.g. a plastics film, a non-woven fabric, aplastics foam, a woven fabric or the like, for covering purposes.

Suitable volatile solvents include, but are not limited to, alcoholssuch as isopropanol and ethanol; aromatics such as xylenes and toluene;aliphatics such as hexane, cyclohexane, and heptane; and alkanoic acidesters such as ethyl acetate and butyl acetate.

An exemplary general method for the preparation of a preferredembodiment is as follows:

1. Appropriate amounts of polysiloxane and rubber adhesives, or polymerssolvent(s), enhancer(s), and organic solvent(s) (for example toluene)are combined and thoroughly mixed together in a vessel.

2. The drug is then added to the mixture and agitation is carried outuntil the drug is uniformly mixed.

3. Small and larger crystals of the drug are then added to the mixtureand thoroughly mixed.

4. The formulation is then transferred to a coating operation where itis coated onto a protective release liner at a controlled specifiedthickness. The coated product is then passed through an oven in order todrive off all volatile processing solvents.

5. The dried product on the release liner is then joined to the backingmaterial and wound into rolls for storage.

6. Appropriate size and shape “systems” are die-cut from the rollmaterial and then pouched.

The order of steps, the amount of the ingredients, and the amount andtime of agitation or mixing may be importance process variables whichwill depend on the specific polymers, drug, cosolvents, and enhancersused in the formulation. These factors can be adjusted by those skilledin the art, while keeping in mind the object of providing a uniformproduct. It is believed that a number of other methods, includingchanging some of the order of steps, can be carried out and will givedesirable results. In addition to having various shapes, the dosageunits produces may come in various sizes. A surface area in the range of1 to 200 cm² is contemplated, and the presently preferred sizes are fromabout 5 to about 60 cm².

Further details and examples of pressure-sensitive adhesives, enhancers,solvents, co-solvents, release liners, backing layers, and otheradditives, as well as transdermal systems generally, suitable inpracticing the invention are described in U.S. Pat. Nos. 5,474,787,5,958,446, 6,024,976, 6,562,363 and 60/488,928, all of which areassigned to Noven Pharmaceuticals, Inc. and incorporated herein byreference.

The present invention is illustrated by the following examples, withoutlimiting the scope of the invention.

EXAMPLES

In the Examples as shown with respect to FIGS. 1 and 2, the effect ofvariations in the crystal size of the drug are determined, indicatingthat by modifying the crystal size of the drug, one can effectivelycontrol permeation rate, onset and profile of the drug in thetransdermal delivery system.

The carrier compositions containing clonidine and frovatriptan wereprepared and coated onto a fluoropolymer release liner and dried for 5minutes at RT and 5 minutes in a 92° C. oven to produce apressure-sensitive adhesive (PSA) carrier composition by dry weight asset forth below.

Example 1 Example 2 Example 3 Silicone PSA (BIO PSA-4302) 85 85 85Polyisobutylene (Vistanex) 10 10 0 Acrylic PSA (DURO-TAK 87- 0 0 102100) Clonidine 5 5 5 Crystal Size of Clonidine 200-250 μm 75 μmDissolved average

Example 4 Example 5 Silicone PSA (BIO PSA-4302) 40 40 Acrylic PSA (Gelva3087) 40 40 Butylene Glycol 5 5 Oleth 3 (Brij) 5 5 Frovatriptan Base 1010 Crystal Size of Frovatriptan Base 1-200 μm 200-250 μm

Determination of drug flux of the described formulations was conductedon a modified Franz Diffusion cell through a disc of stratum corneumobtained from human cadaver skin. The transdermal systems were die-cutpunched, mounted on the disc, and placed on the cell, which contained anisotonic saline solution. The cells were stored at 32° C. for theduration of each flux study while having the solution stirred at aconstant rate of approximately 300 rpm. Samples (n=5) of the solutionwere taken at various time points over the study duration, and drugconcentrations were determined by high pressure liquid chromatography.

FIG. 1 illustrates that the drug from in Example 3, being solubilized orin non-crystallized form, reaches maximum delivery within 24 hoursfollowed by a significant decrease in flux. However, as demonstrated inExamples 1 and 2, which contain crystallized clonidine, a sustainedseven-day delivery at substantially zero order is achievable as comparedto the rapid release of dissolved drug in Example 3. As can be furtherseen from FIG. 1, the larger crystals used in Example 1 produce a lowerpermeation rate (flux) than the smaller crystals used in Example 2.Thus, FIG. 1 shows that crystal particle size contributes to variationsin drug delivery rates.

FIG. 2 further illustrates how drug particle size can be manipulated toachieve variations in drug delivery rates/profiles.

The above description and examples are only illustrative of preferredembodiments which achieve the objects, features, and advantages of thepresent invention, and it is not intended that the present invention belimited thereto.

1. A transdermal drug delivery system comprising a pressure sensitiveadhesive composition which comprises a blend of: (a) one or morepolymers selected from the group consisting of a rubber based polymer,an acrylic based polymer and a polysiloxane; and (b) a pharmacologicallyeffective amount at least one drug for transdermal drug delivery,wherein said at least one drug is (i) solubilized in said pressuresensitive adhesive, (ii) incorporated in said pressure sensitiveadhesive in crystal form having a small crystal size, and (iii)incorporated in said pressure sensitive adhesive in crystal form havinga larger crystal size, wherein the amount of drug solubilized in saidpressure sensitive adhesive, the amount of drug incorporated in saidpressure sensitive adhesive in crystal form having a small crystal size,and the amount of drug incorporated in said pressure sensitive adhesivein crystal form having a larger crystal size are selectively tailored tocontrol the drug delivery rate and profile of the drug from thetransdermal drug delivery system.
 2. The transdermal drug deliverysystem according to claim 1, wherein the one or more polymers comprisesa rubber based polymer which is present in an amount from 5% to 97% byweight of said pressure sensitive adhesive composition.
 3. Thetransdermal drug delivery system according to claim 2, wherein saidrubber based polymer is selected from the group consisting of naturaland synthetic polyisoprene, polybutylene, polyisolyobutylene, styrenebased polymers, styrene block copolymers, butadiene based polymer,styrene/butadiene polymers, styrene-isoprene-styrene block copolymers,hydrocarbon polymers, and halogen-containing polymers.
 4. Thetransdermal drug delivery system according to claim 2, wherein saidrubber based polymer includes polyisobutylene.
 5. The transdermal drugdelivery system according to claim 1, wherein said one or more polymerscomprises a polysiloxanc polymer present in an amount from 5% to 97% byweight of said pressure sensitive adhesive composition.
 6. Thetransdermal drug delivery system according to claim 1, wherein the oneor more polymers comprises a silicone fluid polymer present in an amountof from about 0.5 to about 25% of the pressure sensitive adhesivecomposition.
 7. The transdermal drug delivery system according to claim6, wherein said silicone fluid polymer includes dimethicone.
 8. Thetransdermal drug delivery system according to claim 1, wherein the oneor more polymers comprises at least one acrylic-based polymer present inan amount from 5% to 97% by weight of said pressure sensitive adhesivecomposition.
 9. The transdermal drug delivery system according to claim8, wherein the acrylic-based polymer includes at least 50% by weight ofan acrylate or alkyl acrylate monomer, from 0 to 20% by weight of afunctional monomer copolymerizable with the acrylate or alkyl acrylatemonomer, and from 0 to 40% by weight of other monomers.
 10. Thetransdermal drug delivery system according to claim 1, wherein the drugis selected from the group consisting of scopolamine, estradiol,granisetron, frovatriptan and clonidine.
 11. The transdermal drugdelivery system according to claim 1, wherein the drug includesclonidine.
 12. The transdermal drug delivery system according to claim1, wherein the drug includes frovatriptan.
 13. The transdermal drugdelivery system according to claim 1, wherein the drug is present insaid transdermal drug delivery system in an amount selected from thegroup consisting of (i) about 0.1% to about 50%, (ii) about 0.3% toabout 30%, (iii) about 0.5% to about 15%, and (iv) about 1% to about10%, all by weight of said pressure sensitive adhesive composition. 14.The transdermal drug delivery system according to claim 1, wherein saidsolubilized drug is incorporated in the transdermal drug delivery systemin an amount of from 0.1 to about 50% by weight of the total drugamount.
 15. The transdermal drug delivery system according to claim 1,wherein said small crystal size drug is incorporated in the transdermaldrug delivery system in an amount of from 1 to about 60% by weight ofthe total drug amount.
 16. The transdermal drug delivery systemaccording to claim 1, wherein said larger crystal size drug isincorporated in the transdermal drug delivery system in an amount offrom 2 to about 70% by weight of the total drug amount.
 17. Thetransdermal drug delivery system according to claim 1, wherein the ratioof said small crystal size drug to said larger crystal size drug isabout 2:1.
 18. The transdermal drug delivery system according to claim1, wherein said small crystal size is from about 1 μm to about 200 μm.19. The transdermal drug delivery system according to claim 1, whereinsaid larger crystal size is from about 100 μm to about 2000 μm.
 20. Thetransdermal drug delivery system according to claim 18, wherein saidlarger crystal size is from about 100 μm to about 2000 μm.
 21. Atransdermal drug delivery system comprising a pressure sensitiveadhesive composition comprising a blend of: (a) one or more polymersselected from the group consisting of a rubber based polymer, an acrylicbased polymer and a polysiloxane, present in an amount from 5% to 97% byweight of said pressure sensitive adhesive composition; and (b) apharmacologically effective amount at least one drug for transdermaldrug delivery, wherein said at least one drug is (i) solubilized in saidpressure sensitive adhesive, (ii) incorporated in said pressuresensitive adhesive in crystal form having a small crystal size of fromabout 1 μm to about 200 μm, and (iii) incorporated in said pressuresensitive adhesive in crystal form having a larger crystal size of fromabout 100 μm to about 2000 μm, wherein the amount of drug solubilized insaid pressure sensitive adhesive, the amount of drug incorporated insaid pressure sensitive adhesive in crystal form having a small crystalsize, and the amount of drug incorporated in said pressure sensitiveadhesive in crystal form having a larger crystal size are selectivelytailored to control the drug delivery rate and profile of the drug fromthe transdermal drug delivery system.
 22. A method for transdermallydelivering a drug to a subject in need thereof comprising administeringthe transdermal drug delivery device according to claim 1 to saidsubject.
 23. A method for transdermally delivering a drug to a subjectin need thereof comprising administering the transdermal drug deliverydevice according to claim 21 to said subject.